The present invention relates to a method of making intermediates useful in the synthesis of azalide antibiotics. Azalide antibiotics are useful in the therapy of bacterial infections in mammals.
The method begins with a fragment of the well known antibiotic macrocycle erythromycin A (Ia). ##STR4##
Erythromycin A is cleaved to form an "eastern fragment" which consists of carbons 1 through 10 of the macrocycle.
The eastern fragment exists as an equilibrium mixture of ketone (IIa) and hemiketal (IIb) forms as shown: ##STR5##
The invention comprises a method of converting the prototypical erythromycin fragment(s) into a fragment (hereinafter referred to as the 8a-aza fragment) which is structurally homologous to the azalide antibiotic 9-deoxo-8a-aza-8a-homoerythromycin A, or alternatively into a fragment (hereinafter called the 9a-aza fragment) which is structurally homologous to the azalide antibiotic 9-deoxo-9a-aza-9a-homoerythromycin A. This homology is exact in the case of the 8a-aza fragment and 9-deoxo-8a-aza-8a-homoerythromycin A, and nearly exact in the case of the 9a-aza fragment and 9-deoxo-9a-aza-9a-homoerythromycin A (differing only in the presence of an ethyl group at C9 of the 9a-aza fragment) as can be seen in the formulae which follow: ##STR6##
These fragments are useful intermediates in the synthesis of azalide antibiotics which have high structural homology to 9-deoxo-8a-aza-8a-homoerythromycin A and 9-deoxo-9a-aza-8a-homoerythromycin A in their "eastern" sides, but which are free to diverge in structure by an arbitrary amount in their "western" sides (western side shall be understood to be any portion of the macrocyclic ring not part of the eastern side, as eastern is defined above).